Esters of secondary phenolic amines



P atented 7, 1946 ESTERS OF SECONDARY PHENOLIC AMINES Johannes S. Buck, East Greenbush, N. Y., and Laszlo Reiner, Bloomfield, N. J., assignors to Burroughs Wellcome A; Co. (U. S. A.) Inc., New York, N. Y., a corporation of New York No Drawing. Application September 7, 1944,

Serial No. 553.116

4 Claims.

This application is a continuation-in-part of U. S. application Serial No. 431,222.

This invention relates to esters of substituted phenolic secondary. amines and salts of these esters. One object of the invention is to provide a method of making esters of substituted phenolic secondary amines.

Another object of the invention is to provide a group of compounds having novel and improved properties, particularly for therapeutic or medicinal purposes.

Still another object of the invention is to produce phenolic amines of greater stability and which are less readily oxidized than the corresponding unesterified phenolic amines.

A still further object of the invention is to produce drugs in the form of esterifled phenolic amines which can be given orally on account of the protection afforded the hydroxy group, whereas the corresponding unesterifled compounds are notoriously ineffective when given orally.

The compounds which may be produced according to the present invention may be represented by the following general formula:

where R is a lower allqrl having, for instance, from 1 to 4 carbon atoms, X is a lower alkylene radical having at least 2 and preferably not more than 4 carbon atoms, R is an acyloxy containing, for instance, from 2 to '7 carbon atoms, R is selected from the group consisting of hydrogen, hydroxy, the lower alkyls containing, for instance, from 1 to 4 carbon atoms, the lower alkoxys, such as methoxy or ethoxy, and R and R. is selected from the group consisting of hydrogen and chlorine.

It will be apparent that substances of this type may act within the animal body intwo wayseither through the physiological activity inherent in their original esterifled form or through the gradual hydrolysis of the ester groups. In the latter case the drug administered behaves as a sort of reservoir from which the phenolic compound is continuously supplied so that the inpharmacological investigation that both of these predicted modes of action are indeed manifested,

the lack of suitable chemical methods. In general the amino group-containing an active hydrogen is more ready to react with acid halides and anhydrides than the hydroxyl group. Hence, the

direct acylation of a phenolic secondary amine.

always results in amidation of the nitrogen atom as well as, or in preference to the esterification of the hydroxyl. On the other hand, the amide grouping, once formed, is inherently more stable than the ester type, so that attempts to remove one from a compound containing both result in hydrolysis of the ester as well as or in preference to hydrolysis of the amide portion.

Accordingtc the present invention this difliculty is overcome by carrying out the esteriflcation with compounds in which the hydrogen atom of the secondary amino group is substituted by a benzyl group and subsequently removing this benzyl group by a. specifically developed catalytic hydrogenation which leaves the ester group intact.

The reduction may be carried out with various catalytic metals. Platinum, for instance has been "esters since under slightly acid conditions such as must exist in the presence of salts of weak bases and strong acids, esters react with alcohols to exchange the alcohol groups. Thus catechol diacetate reacts with methanol at room temperature in the presence of a trace of HCl according to the equation:

+2CHiOH +2CH3COOCH:

- omooo H0 and the one or the other predominates accordin as the ester group is one that is hydrolyzed slowly or rapidly. For example, the fatty acid esters are hydrolyzed in general rather fast, the benzoates If such exchange took place to even a slight extent it would interfere seriously with the isolation of a pure product.

In aqueous solutions hydrolysis might also take place though a slower rate might be expected. Furthermore, the toluene produced by the reaction could be expected to form a second layer which might clog the catalyst.

Highly concentrated solutions of lower organic acids are equally unsuitable for the debenzylation step of the present method because of the danger of the formation of an amide.

It has been found that both, the hydrolysis of the ester and the formation of an amide, can be completely avoided if the reduction of the tertiary amines is effected in aqueous solutions of the lower fatty acids, such as acetic acid, propionic acid or butyric acid, containing between 2% and 5.0% by weight of water. Aqueous acetic acid 50- lutions of this typ have given best results.

Previous experience had shown that heat might indeed be necessary to achieve the desired debenzylation as this is the case with amines of the CHQCHI (a) HoOcmcmN CHICIHS acooOcmcnmncm on Io RCOO RCOO

OHrOHzNHCHr Qocon con The phenolic tertiary amines (Ia, Ib) are readily prepared from familiar secondary amines such as N-methyl homoanisylamine, N-methyl homoveratrylamine, etc., by benzylation to the corresponding benzyl tertiary amine followed by demethylation b concentrated hydrochloric acid in a bomb or autoclave.

The monohydroxy type (Ia) can also be prepared conveniently by catalytic reduction of the Schifi base from the corresponding methoxy primary amine followed by methylation of the N-atom by heating with formaldehyde in a formic acid solution and removal of the methoxyl methyl group as above,

Esterification of the types I to the types II is accomplished under various conditions depending upon the acid halide used. Benzoylation is effected. for instance, by shaking with benzoyl chloride in alkaline solution. Acetylation is accomplished most conveniently by refluxing with mix tures of acetyl chloride and acetic anhydride. The carbethoxyl group is best attached by treatment with ethyl chlorocarbonate and an alkaline solution.

The salts of the bases may be made by combining them with an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, succinic acid and the like by the usual methods.

The following list is intended to exemplify, without limiting, the types of compounds obtainable according to the present inventlom.

l. Alpha-methylamino-beta- (4-acetoxyphenyl) ethane hydrochloride 2. Alpha-methylamino-beta- (Z-acetoxyphenyl) ethane 3. Alpha-propylamino-gamma-(2-acetoxyphenyllpropane hydro-bromide 4. Alpha-methylamino-beta-(4-ethylcarbonatophenyl) ethane 5. Alpha-methylamino-gamma-(4-ethylcarbonatophenyl) propane succinate 6. Alpha-ethylamino-beta (4 ethylcarbonatophenyl) butane hydrochloride 7. Alpha-methylamino beta (4 benzoyloxyphenyl) ethane 8. Beta-ethylamino-alpha- (3 benzoyloxyphenyl) propane phosphate 9. Alpha-ethylamino-beta- (4 benzoyloxyphenyl) propane sulfate Alpha-methylamino-beta-(4-ethylcarbonato- 3-chlorophenyl) ethane Alpha-methylamlno -beta-(2- hydroxy 3 acetoxyphenyl) ethane hydrochloride Alpha-methylamino-beta- (4-hydroxy-3 valeroxy-5-chlorophenyl) ethane Alpha-ethylamino-beta-(2-n-butyl 4 acetoxyphenyl) ethane hydrochloride Alpha-methyiamino-beta- (2-methyl-4-ethylcarbonatophenyl) ethane sulfate Alpha-propylamino -beta- 2-ethyl-4-propionoxy-5-chlorophenyl) ethane phosphate Alpha-ethylamino-gamma-(3-methoxy-2-acetoxyphenyl) propane hydrochloride Alpha-ethylamino-beta-(3-ethoxy 4 propionoxyphenyl) ethane maleate Alpha-propylamino-beta (3 benzoyloxyimethoxy-fi-chlorophenyl) ethane hydrochloride Alpha-methylamino beta (3,4 diacetoxyphenyl) ethane hydrochloride Alpha-methylamino beta (3,4 dlacetoxyphenyl) ethane Alpha-methylamino beta (2,5 diaoetoxyphenyl) ethane Alpha-propylamino-alpha (2,3 diacetoxyphenyl) ethane Alpha-methylamino-beta- 2,4-dipropionoxyphenyl) ethane Alpha-methylamino-beta- 3,4-diethylcarbonatophenyl) ethane hydrochloride Alpha-niethylamino-beta- 3,4-diethylcarbonatophenyl) ethane Alpha-methylamino-beta- (2,3 dibenzoyloxyphenyl) ethane Alpha-methylamino-beta- (3,4 dibenzoyloxyphenyl) ethane hydrochloride bonato-Z-chlorophenyl) ethane.

The following examples illustrate methods which may be used according to the invention to 2,4oo,oss

prepare the desired esters of phenolic secondary amines. The examples are not to be taken as limiting the scope of the invention but they are given merely by way of illustration.

EXAMPLE 1 Alpha-methylammo-beta- (4-acetoxyphenyl) ethone hydrochloride acetic anhydride and cc. of acetyl chloride.

In the course of 30 minutes the solid dissolved and shortly thereaiter'the solution became cloudy and deposited a crystalline material. Refiuxing was continued for two hours longer and the acetic anhydride was then blown ofl by a stream of air. The residual solid, 4-acetoxyphenethyl-benzyl methylamine hydrochloride, was washed with acetone and then filtered: it was substantially pure at this point.

Ten g. of this substance was dissolved in 10 cc. of water and added to 40 cc. oi. glacial acetic acid. The solution was reduced with hydrogen in the presence of 6 g. of palladized charcoal (con taining 0.6 g. of Pd). The theoretical amount of hydrogen was absorbed in 2 hours.

extracted with ether. The ethereal extract was dried over KaCOs. filtered oil and precipitated with gaseous hydrogen chloride. A syrup formed which crystallized on scratching and was recrystallized from acetone-ether mixture Seven g. or the hydrochloride thus obtained was reduced in 50 cc. of 80% acetic acid with ptoxide-platinum black, the theoretical amount of hydrogen being taken up. After filtration from the catalyst and evaporation in vacuo a product was obtained which crystallized from acetone ether in platelets and melted at 139' C.

, EXAIPLI 4 Alpha-methvlamino-gamma- (l-ethvlcarbonatophenyl) propane succinate Four hundredths mole (11.7 g.) o! gamma-(4- hydroxyphenyl) propylbenzylmethylamine hydrochloride was carbethoxylated by the method described in Example 3. The product, after drying in ethereal solution and transformation to the hydrochloride, did not crystallize readily. It was therefore dissolved as it was in 50 cc. of 80% acetic acid and hydrogenated over palladized charcoal. The catalyst was filtered ofl and the filtrate taken down in vacuo. The residual hydrochloride was crystallized once from acetoneether and then dissolved in water. From this so- The solution was then filtered and evaporated to dryness in vacuo. The residual solid was dissolved in slightly aqueous acetone and ether and a little acetic acid added. 0n standing the compound crystallized out and was filtered of! and recrystallized from, preferably, aqueous acetoneethyl acetate-ether mixture. The alpha-methylamino-beta (4 acetoxyphenyl) ethane hydrochloride so obtained tormed silky leaves, melting at about 194 C. and giving correct analytical results.

ExAmPLr: 2

Ahaha-methylamino-beta- (Z-acetomyphenyl) ethane Fourteen g ,5 mole) of z-hydroxyphenethylbenzylmethylamine hydrochloride was acetylated as in Example 1. Eleven g. of the product was then reduced with palladized charcoal in 50 cc. of 60% acetic acid and the desired 2-acetoxyphenethylmethylamine isolated also as in Example 1. Further purification was accomplished by recrystallization from acetone-ether mixtures.

EXAMPLE 3 AZpha-methylamino-beta-(4-ethyloarbonatophony!) ethane j bonate being added. Stirring was continued for 10 minutes and the solution was then rapidly lution the base was liberated by addition of sodium carbonate. The oil so formed was taken into ether,- dried briefly over K200: and added to an excess oi'succinic acid in acetone solution yielding the crystalline acid succinate.

Exams: 5

Alphamethylamino-beta- (d-benzoylozyphenul) ethane Nine g. of p-hydroxyphenethyl benzyl methylamine hydrochloride A mole) was benzoylated in an alkaline solution. The base was taken into ether, dried over KzCOa, and precipitated with gaseous hydrogen chloride. After recrystallization from aqueous acetone-ether, 10 g. of the material was dissolved in 50 cc. oi. 50% acetic acid and reduced as in Example 1. The catalyst was filtered of! and the solution evaporated in vacuo, leaving a white solid. This was recrystallized from aqueous acetone-ether mixtures. It crystallized in leaflets and melted at 198 C.

EXAMPLE 6 Alpha-methylamino-beta- (4-ethulcarbonato-3 chlorophenill) ethane The 4 hydroxy-Zi-chlorophenethyl methylbenzyl amine hydrochloride was purified by recrystallization. from alcohol-ether mixtures. 0f the product so obtained, 23 g. was carbethoxylated by the method of Example 3 and the carbethoxy derivative crystallized from aqueous acetone-ether mixtures. The purified material (18 g.) was dissolved in 50 cc. of 95% acetic acid and hydrogenated catalytically with palladized charcoal as in Example 1. and evaporation in vacuo, the desired alphamethylamino beta (4 ethylcarbonato-3-chlorophenyl) ethane hydrochloride was obtained as a solid and crystallized from aqueous acetoneether mixtures.

. Exmrtz'l Alpha-methylamino-beta-(4-hydrozcu-3- valerory-5-chlorophenyl) ethane Ten g. of 3,4-dihydroxy-5-chlorophenethylbenzyl methylamine hydrochloride (prepared by a variation of the common epinine synthesis in the following steps: vanillin 4-hydroxy-3-methoxycinnamic acid+4-hydroxy-3-methoxyhydrocinnamic acid 4-hydroxy-3-rnethoxy-5-chlorohydrocinnamic acidamide NaOC-l 4-hydroxy-3-methoxy 5 chlorophenethylamine and thence to the tertiary (benzyl, methyl) amine as outlined previously, followed by demethylation with concentrated HCl at 160 C.) was heated under reflux with valeric anhydride for three hours. The solution was then evaporated in vacuo and recrystallized from acetone-ether. Only one of the hydroxyl groups, presumably that in the 3 position was found to have been esterlfled. The product was then dissolved in 50 cc. of 80% acetic acid and hydrogenated with palladized charcoal as in Example 1. The catalyst was filtered off, the solution evaporated in vacuo, and the product recrystallized from acetone-ether mixtures.

EXAMPLE 8 il ha-propylamino-beta-(2-ethyl-4-propionoar1r- 5-chlorophenyl) ethane phosphate Thirty-two g. (0.1 mole) of 2-ethyl-4-methoxyphenethylbenzyl propylamine hydrochloride was dissolved in 200 cc. of 6 N HCl and 7.1 g. (0.1 mole) of chlorine gas was bubbled in slowly and with stirring. When the chlorine was virtually all reacted the solution was evaporated in vacuo and the residual solid, the 5-chloro compound, was recrystallized from ethanol-ether mixtures. In two glass bombs 17.7 g. /:o mole) of this material was demethylated by heating at ISO-170 C. for three hours (30 cc. of cone. HCl in each bomb). After opening the bombs the solutions were concentrated in vacuo and the product, 2- ethyl-4-hydroxy-5-chlorophenethylbenzylpropyl amine hydrochloride was recrystallized from alcohol-ethyl acetate mixtures. By refluxing with propionic anhydride and propionyl chloride 13.6 g. was transformed to the propionyl derivative which was crystallized from acetone-ether mixture. Twelve g. (0.03 mole) of this material was dissolved in 50 cc. of 70% propionic acid and hydrogenated with palladized charcoal yielding after filtration, evaporation in vacuo and crystallization from acetone-ether mixtures 2-ethyl- 4-propionoxy-5-chiorophenethyl-n-propylamine lwdrochloride. Six g. of this purified product was then dissolved in water, basified with NaaCOa, taken into ether, and neutralized with an aqueous On filtration from the catalyst acetone solution containing exactly 0.98 g. (0.01 mole) of phosphoric acid. By crystallization from acetone the desired phosphate was obtained in a pure form.

Exam? 9 Alpha-ethulamino-beta- (3.-ethory-4-pmpionoxyphenyl) ethane maleate 3-ethoxy 4 hydroxyphenethylbenzyl ethylamine was prepared from ethyl vanillin by the general route described in Example 7 but without the chlorination step. One-twentieth mole (16.3 g.) thereof was transformed to the propionyl derivative and the product after crystallization from acetone-ether was reduced with palladized charcoal in 75% propionic acid (12 g. of hydrochloride in 50 cc. of solution). The hydrochloride was isolated and crystallized from acetone-ether mixtures. Six (0.02 mole) was dissolved in water, basified with NazCOa, taken into ether and dried over KzCOa. The dry ethereal solution was added to an ethereal solution containing 2.4 g. (cald. 2.32 g.) of maleic acid. The acid maleate crystallized at once and was purified by recrystallization from acetone-ether mixtures.

EXAMPLE 10 Alpha-methylamino-beta-(3,4 diacetoxyphenyl) ethane hydrochloride 3,4 dim e t hoxyphenethylbenzylmethylamine was demethylated by heating for 2 hours at 170 C. in bombs each containing 5 g. of amine hydrochloride and 30 cc. of concentrated HCl. with an atmosphere of CO3. 10.8 g. of the product was acetylated as in Example 1 with 30 cc. of acetic anhydride and 15 cc. of acetylchloride. The reaction and purification were accomplished as in Example 1. 8.4 g. of the product was dissolved in 50 cc. of acetic acid and hydrogenated with palladized charcoal. After approximately the theoretical amount of hydrogen had been taken up, the solution was filtered, the solvent removed in vacuo, and the residual alphamethylamino-beta-(3,4-diacetoxyphenyl) ethane hydrochloride recrystallized from acetone-ethyl acetate-ether mixture until pure. The compound forms small glittering leaves or plates, melting at about 143 C. and giving correct analytical results.

ExAMrLa 11 Alpha-methylamino-beta-(2,5 diacetoryphenyl) ethane One twentieth mole (14.8 g.) of 2,5-dihydroxyphenethylbenzylmethylamine hydrochloride (obtained by demethylating the corresponding 2,5- dimethoxy compound by the procedure described in Example 10 for the 3,4-dimethoxy compound) was acetylated by refluxing with acetylchloride and acetic anhydride as in Example 10. The product was crystallized from acetone-ether mixtures, 15 g. (0.04 mole) was hydrogenated with palladized charcoal in 50 cc. of 98% acetic acid with approximately 0.04 mole of hydrogen was absorbed. The catalyst was filtered off and the solution evaporated in vacuo. The product was purified by crystallization from aqueous acetoneether mixture.

EXAMPLE 12 Alpha methylamino-beta (2,4 dipropz'onory phenyl) ethane Fifteen g.(0.05 mole) of 2,4-dihydroxyphenethylbenzylmethylamine hydrochloride was acylated by refluxing with a mixture oipropionyl chloride and propionic anhydride. The product, 2;4-dipropionoxyphenethylbenzylmethylamine hydrochloride was crystallized from acetone-ether mixture. Twelve g. (0.03 mole) of this was dissolved in 50 cc. of 85% propionic acid and hydrogenated with palladized charcoal and hydrogen. After absorption of hydrogen had stopped (0.03 mole taken) the solution was filtered from the catalyst and evaporated in vacuo. The residual syrup dissolved in acetone and crystallized on addition of ether.

' EXAMPLE 13 Alpha-methylamino-beta- (3,4-diethylcarbonato phenyl) ethane hydrochloride Nine and one-half g. of 3,4-dihydroxyphenethyl' methylbenzylamine (see Example hydrochloride was dissolved in 40 cc. of water with cooling and stirring and with an atmosphere of nitrogen. To this was added in all 21.2 g, (6 mols.) of ethyl chlorocarbonate and 8.1 g. (7 mols) of sodium hydroxide in 10% aqueous solution. The two reagents were added in portions and alternately so that the solution was at times acid and at times alkaline. Towards the end of the reaction the oily product remained substantially undissolved even when the solution was alkaline. The reaction mixture was then extracted rapidly with ether and dried over KzCOa. The hydrochloride (8.7 g.) was obtained by passing gaseous HCl into the ethereal solution and was not obtained crystalline but was dissolved in 50 cc. of 75% acetic acid and reduced as in Example 1. After filtration the solution was evaporated in vacuo leaving a thick syrup which was dissolved in acetone from which crystals were formed on addition of ether. This compound, alter purification by crystallization from acetoneethyl acetate-ether mixture forms silky leaves. melting at about 115 C.

EXAMPLE 14 Alpha methylamino-beta (2,3 dibenzoyloxy phenyl) ethane Nine g. (0.03 mole) of 2,3-dihydroxyphenethylbenzylmethylamine was benzoylated in an alkaline solution. The hydrochloride of the dibenzoyl derivative was crystallized from acetone-ether mixture. Ten g. of the product (0.02 mole) was hydrogenated with palladized charcoal in 85% acetic acid yielding the desired product.

Examrne 15 Alpha methz/Zamino beta (3,4 dibenzoyloxyphenyl) ethane hydrochloride in colorless microprisms and melted at l63-4 C.

EXAMPLE 16 Alpha-methylamino-beta- (4,5-diethylcarbonato Z-chlorophenyl) ethane Thirty-three g. (0.1 mole) of 2-chloro-4,5-dihydroxyphenethyl benzylmethylamine hydrochloride (prepared from homoveratryl benzyl methylamine by chlorination and demethylation as shown in Example 6) was carbethoxylated by the method described in Example 13. The product was crystallized from aqueous acetone-ether. Seventeen g. of the material so purified was dissolved in 50 cc. of butyric acid and hydrogenated catalytically in the presence of palladized charcoal. After the required amount of hydrogen (0.03 mole) had been absorbed, the reduction was stopped, the catalyst filtered off andthe flltrate evaporated in vacuo. The residue. which was the desired alpha-methylamino-beta-4,5-diethylcarbonato 2 chlorophenyl) ethane hydrochloride, was crystallized from aqueous acetoneether mixtures.

. We claim:

1. An ester of a phenolic secondary amine represented by the formula:

sisting of alpha-methylamino-beta (3,4 diben-- zoyloxyphenyl) ethane and its salts.

JOHANNES S. BUCK. LASZLO REINER. 

